1. Field of the Invention
The present invention relates to a process for the microbial production of pyrrolo-quinoline quinone (hereinafter referred to as PQQ).
2. Description of the Related Art PQQ has the following formula: ##STR1## and can be reversibly reduced to a reduced type PQQ (PQQH.sub.2) having the following formula: ##STR2## On the basis of this property, PQQ has an ability to convert apo-type quinoenzymes to the holo-type thereof. For example, PQQ acts as a coenzyme for methanol dehydrogenase in methanol-utilizing bacteria, alcohol dehydrogenase, aldehyde dehydrogenase, glycerol dehydrogenase, glucose dehydrogenase, or the like in acetic acid bacteria. PQQ is also physiologically important as a coenzyme for copper containing amine oxidase of animal, plant or microbial origin, amine dehydrogenase or choline dehydrogenase, or other various kinds of oxidoreductases which are inhibited by carbonyl reagents.
Moreover, PQQ may be a very important substance having vitamin actions because it acts as a coenzyme for important enzymes as described above, taking as an analogy the fact that coenzymes for other oxidoreductases and transferases, such as thiamine pyrrophosphate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, pyridoxal phosphate, flavin adenine dinucleotide, and flavin mononucleotide have to be taken in as vitamin, such as vitamin B.sub.1, nicotinic acid, vitamin B.sub.6 , and vitamin B.sub.2 , respectively. On the basis of the above-mentioned physiological importance, PQQ is useful for pharmaceutical purposes.
Conventionally, for the production of PQQ, chemical synthetic processes are known (see, for example, J. Am. Chem. Soc. Vol. 103, 5599-5600 (1981)). However, these chemical synthetic processes have various disadvantages. For example, the processes are time-consuming due to the necessity for multi-reaction steps, require complicated operations to remove many kinds of by-product isomers derived from the reactions, and provide a rather low yield of PQQ.
To overcome the above-mentioned disadvantages of the chemical synthetic processes, there has been presented a biological process for the production of PQQ wherein cells of a microorganism are cultured in a medium to accumulate PQQ and related compounds, and the accumulated PQQ is recovered by, for example, extraction with solvents (see Japanese Unexamined Patent Application (Kokai) No. 59-113896 published on June 30, 1984), or simple chromatographic method on ionexchangers (see, for example, Agri. Biol. Chem. Vol 48, 561-565 (1984)).
Therefore, a new process for the production of PQQ, which is more practical and economical, is desired.